Functional ultrasound neuroimaging: a review of …fultrasound.eu/wp-content/uploads/2018/02/CurrentOpinion...Functional ultrasound neuroimaging: a review of the preclinical 1 and

Functional ultrasound neuroimaging: a review of thepreclinical and clinical state of the artThomas Deffieux1,2, Charlie Demene1,2, Mathieu Pernot1,2 andMickael Tanter1,2

Available online at www.sciencedirect.com

ScienceDirect

In the last decade, ultrasound imaging has gained new

capabilities and produced new insights in the field of

neuroscience. The development of new concepts, such as

ultrafast ultrasound, has enhanced Doppler sensitivity by

orders of magnitude and has paved the way for ultrasonic

functional neuroimaging. In this review, we position ultrasound

in the field of neuroimaging and discuss how it complements

current tools available to neurobiologists and clinicians.

Addresses1 Institut Langevin, CNRS, ESPCI Paris, Inserm, PSL Research

University, Paris, France2 Inserm Technology Research Accelerator in Biomedical Ultrasound,

Paris, France

Corresponding author: Tanter, Mickael ([email protected])

Current Opinion in Neurobiology 2018, 50:128–135

This review comes from a themed issue on Neurotechnologies

Edited by Anikeeva and Luo

https://doi.org/10.1016/j.conb.2018.02.001

0959-4388/ã 2018 Published by Elsevier Ltd.

IntroductionThe longstanding quest to visualize the brain’s complex

organization and interconnections has led to major dis-

coveries in modern neuroscience and neurology. Beyond

anatomical imaging, the advance of technologies in the

last decades has enabled the first dynamic images of the

brain in action [1].

The gold standard of functional brain imaging is undoubt-

edly functional magnetic resonance imaging (fMRI) to

measure blood oxygen level-dependent (BOLD) signals

on high field MRI scanners [2]. Since deoxygenated

hemoglobin is paramagnetic while oxygenated hemoglo-

bin is diamagnetic, blood deoxygenation introduces a

magnetic signal variation, the BOLD signal. The BOLD

signal is indirectly related to neuronal activation through

neurovascular coupling. fMRI is available for human use

and is non-invasive and non-ionizing. Its primary draw-

backs both for preclinical and clinical imaging are its


portability, machine costs, maintenance and accessibility

[3]. Furthermore, limited sensitivity and patient stress in

the confined and noisy magnet are of concern [4].

Position emission tomography (PET) is another func-

tional imaging technique that uses injected radioactive

and biologically active tracers, such as fluorodeoxyglucose

(FDG), to image brain molecular processes; this enables a

visualization of the consumption of glucose related to

brain metabolism [5]. Positron Emission Tomography

computes a 3D reconstruction of the positron-emitting

radionuclides concentration from the pairs of gamma rays

they emit indirectly. Positron Emission Tomography

(PET) is a powerful and highly sensitive nuclear imaging

modality but requires dedicated and secured facilities due

to the radioactive nature of the tracers used. PET suffers

from a poor spatial resolution and must be combined with

a complementary imaging modality, such as MRI or

Computed Tomography (CT), for anatomical imaging.

Finally, optical imaging techniques are fast and provide

excellent spatiotemporal resolution. These can be used to

image blood flow variations at different scales: from the

submillimeter resolution with intrinsic optical imaging to

a micrometer resolution with two-photon microscopy.

Calcium imaging, which requires a genetically engi-

neered animal model, allows spectacular views of neuron

firing with high spatiotemporal resolution for surface

imaging or in transparent samples such as zebrafish [6].

In that case, fluorescent molecules are used as calcium

indicators as they respond to the binding of Ca2+ ions by

changing their fluorescence properties. However, the

limited penetration depth usually confines it to the sur-

face of the cortex. Optics can be used at higher depths at

the cost of a substantial loss of spatial resolution due to

light scattering in tissues [7]. For example, functional

near-infrared spectroscopy, which measures the level of

blood oxygenation through the absorption of diffused

near infrared light at different wavelengths, can be

applied on neonates or young children through the skull

but is limited to cortex imaging with centimeter spatial

resolution [8].

Fundamental barriers of ultrasound imaging in terms of

temporal and spatial resolutions have recently been bro-

ken [9,10]. These paradigm changes led to functional

brain information using neurovascular coupling (Figure 1).

Interestingly, such functional ultrasound (fUS) neuroim-

aging is a stand-alone ultrasound technique that provides

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Functional ultrasound neuroimaging: a review Deffieux et al. 129

Figure 1

Imagingplane

UltrasonicProbe

Fontanel

Neonateneuroimaging

Peroperativeneuroimaging

EEG compatibility

Animal models

Awake &Freely moving

SuperresolutionAngiography

3D Functional imaging

Brain connectomics

Portable scanner

Current Opinion in Neurobiology

The main applications and features of functional ultrasound (fUS) imaging. fUS imaging provides (i) a compatibility with a wide range of animal

models for preclinical studies, (ii) the ability to image awake and freely moving animals, (iii) possibility to combine with super-resolution ultrasound

localization microscopy, (iv) possible extension to 3D imaging, (v) functional connectivity mapping for brain connectomics, (vi) translation to clinical

neuroimaging in human neonates or (vii) peroperative neuroimaging during brain surgery and (viii) EEG compatibility for EEG-fUS recordings.

high sensitivity imaging of cerebral blood volume (CBV)

changes for whole brain imaging without contrast

agents [11].

Ultrasound-based functional imagingtechniquesNeurovascular coupling

Similar to all neurofunctional imaging techniques based

on metabolic or hemodynamics measurements, functional

ultrasound is limited by the spatiotemporal features of

neurovascular coupling as it measures CBV changes. CBV


is a pertinent parameter for functional imaging that is

already used by other modalities such as intrinsic optical

imaging or CBV-weighted fMRI. The spatiotemporal

extent of CBV response was extensively studied

thanks to these techniques [12], and the spatial resolution

of sensory-evoked CBV response can go down to one

cortical column (�100 mm). Temporally, the CBV

impulse response function was measured to typically

start at �0.3 s and peak at �1 s in response to ultrashort

stimuli (300 ms), which is much slower than the underly-

ing electrical activity.


130 Neurotechnologies

Functional transcranial Doppler (fTCD)

Ultrasound Doppler imaging has long been used to obtain

basic functional measurements of brain activity using

blood flow. In functional transcranial Doppler sonogra-

phy, a low-frequency (1–3 MHz) transducer is used

through the temporal bone window with a conventional

pulse Doppler mode to estimate blood flow at a single

focal location. The temporal profile of blood velocity is

usually acquired in main large arteries such as the middle

cerebral artery (MCA). The peak velocity is measured

and compared between rest and task conditions or

between right and left sides when studying lateralization

[13]. However, due to its restriction to global effects in

large vessels and single point measurements, fTCD lacks

true neuroimaging capabilities.

Power Doppler and contrast ultrasound imaging

Power Doppler is a Doppler sequence that measures the

ultrasonic energy backscattered from red blood cells in

each pixel of the image. Power Doppler provides no

information on blood velocity but is proportional to blood

volume within the pixel. However, conventional power

Doppler imaging lacks sensitivity to detect small arter-

ioles/venules and thus is unable to provide local neuro-

functional information through neurovascular coupling

[14]. Adding acoustic contrast agents (microbubbles) to

the blood stream boosts the sensitivity of conventional

power Doppler imaging and enables the detection of

coarse brain activation in various areas of the brain [15].

Ultra-fast ultrasound and fUS imaging

fUS imaging relies on ultrafast imaging scanners [9] able

to acquire images at thousands of frames per second,

thus boosting the power Doppler signal-to-noise ratio

(typically over 50-fold) without any contrast agents

[14]. Instead of the line per line acquisition of conven-

tional ultrasound devices, ultra-fast ultrasound takes

advantage of successive tilted plane wave transmissions

that are afterward coherently compounded to form images

at high frame rates. The sensitivity was recently even

further improved using multiple plane wave transmis-

sions [16] and advanced spatiotemporal clutter filters for

better discrimination between low blood flow and tissue

motion [17�].

This signal boost enables the sensitivity required to map

subtle blood variations in small arterioles (down to 1 mm/

s) related to neuronal activity, whereas conventional

power Doppler is limited to imaging major cerebral

arteries (several cm/s) [9]. fUS neuroimaging has a typical

50–200 mm spatial resolution depending on the ultra-

sound frequency used [14]. It features a temporal resolu-

tion in the tens of milliseconds, can image the full depth

of the brain and can provide 3D angiography [18�]. fUS

imaging requires no calibration and nearly no setup time.

It uses miniaturized probes to enable whole-brain imag-

ing in awake and freely moving rodents [19��].


fUS research platforms require custom sequences pro-

gramming, dedicated high-performance GPU beamform-

ing software with a high data transfer rate (several GBytes

per second) and miniature high-frequency ultrasound

probes to perform live fUS imaging. Future commercial

implementations through specialized hardware and soft-

ware should enable fUS to rapidly expand in utility for the

neuroscience community.

Functional photoacoustic computed tomography

Using laser devices, the photoacoustic effect can be

leveraged to enable molecular imaging of optical contrast

at the ultrasound resolution [20]. The laser is used to

illuminate the brain while the strong light absorption by

red blood cells creates a sharp localized temperature

increase, which in turn generates ultrasonic waveforms.

This latter signal is recorded by a tomographic ultrasound

array and was recently able to detect sensory-evoked

activation in rats [21]. Usually requiring a complex setup

with a high-power pulsed laser, water-filled tank and

ultrasound ring, recent progress has nonetheless been

achieved toward wearable probes for awake imaging

[21] and integrated whole body solutions [20]. Due to

its sensitivity to optical contrast agents, photoacoustic

imaging could one day use calcium probes to perform

calcium imaging at the ultrasound resolution and depth

[22] even in small animal models (Figure 2).

Preclinical applications of functionalultrasound neuroimagingIn 2011, fUS technique was demonstrated for imaging of

activation of the barrel cortex following whisker stimula-

tion in rats [11]. CBV images are then correlated with the

stimulus pattern, and activated regions are overlaid with a

state-of-the-art brain atlas (Figure 3d). In the same paper,

spatiotemporal dynamics of epileptiform seizures were

filmed showing cortical spreading depression propagating

throughout the whole brain (Figure 3e).

Chronic imaging and noninvasiveness

Several animal preparations were proposed for fUS. Ini-

tially, a craniotomy was performed before the experi-

ments and an experiment was performed under isoflurane

anesthesia [11]. For chronic imaging, a thinned skull

procedure was later proposed, allowing several weeks

of imaging [19��,23]. In Sieu et al. [19��], a thin layer of

polymethylpentene (PMP) with a high ultrasonic trans-

mission coefficient and very low ultrasonic absorption was

used to replace the bone. This allowed maintaining

excellent imaging quality along with implanted electro-

des in the animals for more than a year. In Rungta

et al. [24�], a polished PMP layer transparent to both

visible light (>93%; haze <5%) and in the high UV-range

(>300 nm) and ultrasound was used to combine fUS with

optogenetics and two-photon imaging.



Figure 2

High

FNIRS

FMRI

PET

Whole Brain Imaging

Porta

bility

Local Brain Imaging

Spatial Resolution

Tem

pora

l Res

olut

ion

FunctionalUltrasound

OpticalImaging

ImplantedEEG

MEG

Surface

EEG

High

Low

LowLow High


Main brain functional imaging techniques on a three-axis chart (temporal resolution, spatial resolution, portability). Techniques were separated

between local and whole-brain imaging. Functional ultrasound fills a gap between whole brain imaging and microscopy, as well as between fMRI

and Optics.

Tiran et al. demonstrated the feasibility of performing

functional imaging directly through the skull in mice and

young rats until 35th postnatal day (P35) [25]. Using

microbubble contrast agents, Errico et al. [26] further

demonstrated non-invasive fUS through the adult rat

skull. Regarding anesthetics, a mix of ketamine/Domitor

is often preferred to isoflurane as inhalable anesthetics

can cause an increase in cerebral blood flow caused by

reduced cerebrovascular resistance.

Full brain accessibility, 3D imaging and optogenetics

Extensive studies have been performed for somato-sen-

sorial stimulations. Olfactory stimulation in rats was dem-

onstrated in Osmanski et al. [27], who exposed the ani-

mals to two different molecules while imaging the

anterior piriform cortex, which is a challenging structure

to image using fMRI due to nearby air cavities. Visual

stimulation and retinotopies were also investigated in

Gesnik et al. [28�] who applied varying visual patterns

to study the activation of the superior colliculus, the

lateral geniculate nuclei, and the visual cortex. Such

visual stimulation was later reproduced in mice, starling

birds and very recently in 3D in pigeons using the same

approach and isoflurane anesthesia [29]. In Osmanski

et al., fUS was used in conjunction with optical fibers

to demonstrate the vasodilating effect of light in geneti-

cally intact mice [24�]. Massive hyperemia after cardiac


arrest and resuscitation was also investigated in a rabbit

model [40].

Functional imaging in awake animals

One key aspect of fUS is its portability. First, the setup

can be easily moved into animal facilities, which is in

contrast to fMRI scanners. More importantly, the probe

weight allows for experiments in awake and freely mov-

ing subjects. This removes the compounding effects of

anesthesia and facilitates behavior studies.

The first studies were performed on freely moving rats

using miniaturized probes and head implants. In Sieu

et al. [19��], a hybrid setup with a motorized miniaturized

probe, implanted electrodes and acoustically transparent

skull prosthesis was proposed. This setup allowed func-

tional activation studies in awake animals in combination

with electrophysiological recordings anywhere in the

brain using implanted electrodes. The method was used

to study spatiotemporal initiation and the evolution of

seizures in epileptic GAERS rat models in conjunction

with EEG recordings. In the same work, rats running in a

maze were imaged to study locomotion by correlating the

intra-hippocampal EEG theta band with vascular flow

patterns. Merging real time data from fUS and another

complimentary modality, such as electrophysiological

recording, opens numerous possibilities [30]. Urban



Figure 3

Ultrasensible power DopplerFreely moving setups Functional neuroimaging Functional connectivity

Mouse

Rat

Bird

Rabbit

Ferret

Primate

[24] [25]

[19,23]

[24,25]

Microbubbles [26]Young rats <P35 [25,34]

[15,23]

[24]

[29]

[40]

[32,39]

[11,14,18,19,26,27]

[32,39]

[29]

[11,14,18,23,25–27,28,34]

[40] (post cardiac arrest resuscitation)

CraniotomyThin-skullTranscranialfUS awakefUS anesthesized

S1Sh-LS1HL-L

S1HL-RS1Sh-R

M1-LM2-L

M2-RM1-R

Hip-RHip-L

Thal-LThal-R

RSD-L

RSD-RRSGc-RRSGc-L

S1S

h-L

S1H

L-L

S1H

L-R

S1S

h-R

M1-

LM

2-L

M2-

RM

1-R

Hip

-RH

ip-L

Tha

l-LT

hal-R

RS

D-L

RS

D-R

RS

Gc-

RR

SG

c-L

(a)

(b)

(g)

(f)

(d)(c)

(e)


Preclinical applications of fUS imaging. Setups for awake rats [19��] (a) or mice [25] (b). (c) Ultra high-sensitivity Doppler allows whole-brain

imaging in rats [14]. (d) Hyperemia induced by whiskers stimulation in the barrel cortex and in the ventral posterior medial nucleus [11]. (e)

Propagation of an epileptiform seizure in the rat brain [11]. (f) 3D reconstruction of the activated visual system of an anesthetized rat [28�]. (g)

Resting state connectivity matrix in an anesthetized rat. The anti-diagonal represents the interhemispheric functional coupling [33]. Lower panel:

different protocols and animal models tested.

et al. [31] used rats running within a corridor and demon-

strated visual and whisker stimulations with real time

activation inside the cortex or in subcortical structures

such as the thalamus.

In Tiran et al. [19��], even smaller transcranial probes

permitted experiments in freely moving mice. Barrel

cortex activation was demonstrated following manual

whisker stimulation. The auditory tract of awake ferrets

was imaged when listening to different high-pitch

tones, enabling the mapping of the tonotopy of auditory

cortex and thalamic nuclei with a 100 mm resolution

[32,39].

Finally, the supplementary high field (SEF) of trained

primates performing saccades and antisaccades visual

tasks was very recently demonstrated and showed a

30% increase of blood flow in parts of the SEF during

tasks compared to baseline (Dizeux A, et al., IEEE

Ultrasonics Symposium, 1948–5727, Washington, DC,

Nov. 2017).


Brain connectomics

Similarly to resting state fMRI, functional connectivity

was measured in rats by Osmanski et al. [33] using fUS,

yielding high resolution (100 mm) brain connectivity

matrices. This protocol was later used to study the func-

tional connectivity in rat pups following a low protein diet

in their mother [34]. The diet induced intrauterine

growth restriction and a loss of corpus callosum myelina-

tion detected on the connectivity matrices obtained by

fUS. It could thus become a very convenient tool to study

preclinical brain connectomics for drug development and

screening.

Clinical application of fUS imagingEarly in-human neurofunctional studies using ultrasound

were based on the use of only two ultrasonic transducers

placed on each temple window (Figure 4a), enabling the

assessment of cerebral blood flow differences in the left

and right Median cerebral artery (MCA) during a later-

alized cognitive task. This was used to show that language

functions were less predominantly localized in the left



Figure 4

TCD Lateralization Studies Human Neonate fonctional imaging Human Intraoperative fonctional imaging (a)

(b)

(c) (d)

(f)

(g)

(h) (i)(e)

Imagingplane

UltrasonicProbe

Fontanel

80

60

60

–60

UfD

sig

nal [

%]

UfD

sig

nal [

%]

40

40

–40

20

20

–20

0

0

–20

0min +500

ROIs1

Seizure

23

Inferior

AnteriorSuperior

Posterior

Correlation coefficient

0

0

00

2530

1

Dep

th (

mm

)

Width (mm)

110Time (s)

220

0 110Time (s)

220

Stimulus ON

OFF

Left Handedness R

ight

Left Language Right

Num

ber

of S

ubje

cts


Clinical neuroimaging using ultrasound. (a) Conventional transcranial Doppler imaging. (b) Degree of language lateralization in relation to

handedness (from Ref. [28�]). (c) Ultrasonic probe for neurofunctional Ultrasound on a neonate fontanel. (d) Ultra high-sensitivity Doppler image

acquired through the fontanel. (e) Relative changes in CBV occurring after 500 s. (f) 2D mapping of the hyperemia during and after the seizure

[29]. (g) Ultrasonic probe positioned on the brain during open-skull surgery. (h) Temporal profiles during a motor task in the motor cortex (top) and

surrounding areas (bottom). (i) Correlation maps with the stimulus pattern (red line in h) depicts the implicated motor cortex [31].

hemisphere in families with a high rate of left handedness

(Figure 4b in [35]). fUS took this to the next level by

translating 2D functional imaging into clinical setting in

neuropediatry and neurosurgery. In both cases, the use of

a natural anatomic window, that is, the transfontanellar

window, (Figure 4c,d) or craniotomy (Figure 4g) provides

high-quality brain images in humans. In preterm neo-

nates, fUS non-invasively imaged brain activity during

different sleep phases and seizures [36��], showing local

variations in epileptic activity (Figure 4e,f). Its temporal

and spatial resolution unveiled a slow propagative phe-

nomenon after epileptic activity, corroborating previous

in vitro brain slices experiments [37]. In neurosurgery, the

technique was able to achieve real-time cortical func-

tional mapping (Figure 4h) during tumor resection [38��],permitting in-depth delineation of cognitive areas and

avoiding the removal of functionally essential structures

(Figure 4i). In the future, transtemporal imaging could

potentially enable fully non-invasive fUS on human

adults and could extend the clinical domain of fUS.

Conclusion and perspectivesAs a neuroimaging modality, functional ultrasound offers

a unique combination of spatiotemporal resolution, sen-

sitivity, portability, and features that domains of bridge


optical and fMRI techniques. Ultrasound can be used

non-invasively on neonates through the fontanel window

and through the skull in mice. In other configurations

with thicker skulls, contrast agents can be injected to

ensure noninvasiveness; alternatively, a special skull

preparation such as craniotomy or thinned skull proce-

dure is possible. The technique is highly transportable

(being in a form factor close to that of a conventional

ultrasound machine) and can thus be moved to patient

rooms, into wet labs or animal facilities without any

recalibration. The technique was demonstrated to be

compatible with simultaneous electrophysiology record-

ings, optogenetics and even PET scans. Moreover, the

dimensions of probes and cables have been reduced to

enable experiments in awake and freely moving rodents.

The technique currently suffers from limitations: tran-

scranial imaging without contrast agents remains an issue

except for in mice or niche applications. Additionally,

experiments in freely moving mice need further minia-

turization, and the technique remains primarily two-

dimensional. Preclinical fUS imaging is envisioned to

spread widely across the neurobiology labs thanks to

optimized and easy-to-use setups. This wide clinical

dissemination will prompt researchers to address the issue

of transcranial ultrasonic propagation in the adult brain.



Conflict of interest statementTD, MP, MT are co-founders and shareholders of

Iconeus company.

AcknowledgementsThis work was supported by a research grant from the European ResearchCouncil under the European Union’s Seventh Framework Program (FP7/2007-2013)/ERC Advanced grant agreement n� 339244-FUSIMAGINE andby the Inserm Technology Research Accelerator in Biomedical Ultrasound.

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This publication presents the first clinical proof of non-invasive fUSimaging of brain activity in humans. Ultrafast ultrasound imaging isperformed through the fontanel of human neonates at bedside. Theestimation of cerebral blood volume variations in small vessels permitsto image the 2D spatiotemporal dynamics of epileptic seizures in com-bination with surface EEG recordings in preterm babies. fUS neuroima-ging of different sleep phases is also presented in newborns.

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Imbault M, Chauvet D, Gennisson J-L, Capelle L, Tanter M:Intraoperative functional ultrasound imaging of human brainactivity. Sci Rep 2017, 7:7304.

By imaging small variations of cerebral blood volume in trepanned humanpatients undergoing tumor resection, the authors demonstrate for the firsttime the ability of fUS imaging to image deep brain activity in manydifferent regions of the motor and somatosensorial cortex. It provides aproof of concept of cortical functional mapping based on fUS imagingwithout electric stimulation. These results demonstrate fUS imagingcould become a portable and high resolution neuroimaging modalityduring brain surgery.

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